Elsevier

The Lancet

Volume 362, Issue 9395, 8 November 2003, Pages 1517-1526
The Lancet

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Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial

https://doi.org/10.1016/S0140-6736(03)14738-1Get rights and content

Summary

Background

Multiple sclerosis is associated with muscle stiffness, spasms, pain, and tremor. Much anecdotal evidence suggests that cannabinoids could help these symptoms. Our aim was to test the notion that cannabinoids have a beneficial effect on spasticity and other symptoms related to multiple sclerosis.

Methods

We did a randomised, placebo-controlled trial, to which we enrolled 667 patients with stable multiple sclerosis and muscle spasticity. 630 participants were treated at 33 UK centres with oral cannabis extract (n=211), Δ9-tetrahydrocannabinol (Δ9-THC; n=206), or placebo (n=213). Trial duration was 15 weeks. Our primary outcome measure was change in overall spasticity scores, using the Ashworth scale. Analysis was by intention to treat.

Findings

611 of 630 patients were followed up for the primary endpoint. We noted no treatment effect of cannabinoids on the primary outcome (p=0·40). The estimated difference in mean reduction in total Ashworth score for participants taking cannabis extract compared with placebo was 0·32 (95% CI −1·04 to 1·67), and for those taking Δ9-THC versus placebo it was 0·94 (−0·44 to 2·31). There was evidence of a treatment effect on patient-reported spasticity and pain (p=0·003), with improvement in spasticity reported in 61% (n=121, 95% CI 54·6–68·2), 60% (n=108, 52·5–66·8), and 46% (n=91, 39·0–52·9) of participants on cannabis extract, Δ9-THC, and placebo, respectively.

Interpretation

Treatment with cannabinoids did not have a beneficial effect on spasticity when assessed with the Ashworth scale. However, though there was a degree of unmasking among the patients in the active treatment groups, objective improvement in mobility and patients' opinion of an improvement in pain suggest cannabinoids might be clinically useful.

Introduction

Of the many symptoms encountered in multiple sclerosis, muscle spasticity (muscle stiffness as a result of increased pyramidal tone) and spasms occur in up to 90% of patients at some point. This symptom often leads to considerable distress from pain, reduced mobility, and interference with activities of daily living. Other disabling features of the disease include ataxia and tremor in up to 80% of patients, and sensory symptoms, including pain, in up to 50%.1 Lower urinary tract dysfunction is present in more than 90% of people with long-standing multiple sclerosis,2 with the most frequent symptoms being urinary frequency and urgency.3 Although many symptoms resolve in the remitting phase of multiple sclerosis, spasticity, weakness, ataxia, and bladder symptoms are often characteristic of progressive disease and tend to worsen over time.

Symptomatic therapy often provides inadequate relief and can be limited by toxicity. As a consequence, people with multiple sclerosis have experimented with many alternative therapies, including cannabis, to ease their physical problems.4, 5 There is much anecdotal suggestion that cannabis and its major components, the cannabinoids, have beneficial effects on disease-related pain, bladder symptoms, tremor, and particularly spasticity,6 but little scientific evidence exists for their efficacy. There is widespread unlicensed and often illegal use of cannabinoids in multiple sclerosis, involving various formulations and routes of administration, and estimates suggest7 that between 1% and 4% of patients in the UK use cannabis for symptom relief.

The plant Cannabis sativa is complex and has more than 60 oxygen-containing aromatic hydrocarbon compounds, known as cannabinoids. Most of their effects seem to be mediated through cannabinoid receptors, two types of which have been isolated and cloned: CB18 and CB2.9 CB1 receptors are distributed widely in the nervous system, and seem to have a general role in the inhibition of neurotransmitter release, whereas CB2 receptors are mainly found on cells of the immune system. The identification of a range of endogenous cannabinoids, the most important of which are thought to be 2-arachidonoylglycerol and arachidonoylethanolamide (anandamide),10 has also provoked considerable interest, and there is some evidence11, 12 that cannabinoids have a neuroprotective action.

Four small, randomised, double-blind, placebocontrolled studies13, 14, 15, 16 have been undertaken to assess the effect of cannabinoids on spasticity related to multiple sclerosis, the largest of which16 was a crossover study of 16 patients. The results suggest that cannabinoids produce subjective symptomatic improvement, but provide no objective evidence for efficacy. Our aim was to ascertain whether either Δ9-tetrahydrocannabinol (Δ9-THC) or an ethanol extract of whole cannabis is effective for the treatment of spasticity and a range of other disease-related symptoms in patients with multiple sclerosis.

Section snippets

Patients

Between December, 2000, and October, 2002, we enrolled patients aged 18–64 years with clinically definite or laboratory-supported multiple sclerosis who, in the opinion of the treating doctor, had had stable disease for the previous 6 months, with problematic spasticity (Ashworth score of ⩾2 in two or more lower limb muscle groups). Since cannabinoids can potentially affect cardiac function (reducing heart rate and blood pressure), the exclusion criterion of ischaemic heart disease and the

Results

Figure 1 shows the trial profile. Of the 630 patients included in the intention-to-treat analysis, follow-up data on the primary outcome was obtained for 611 (97%). Completion and return of data for the secondary outcome measures was also generally high, with data available for analysis from 84–91% of patients, including for the four questions posed at the end of study.

Table 2 shows the baseline characteristics of the participants. Patients' demographics in the intention-to-treat sample were

Discussion

Treatment with cannabinoids did not improve spasticity associated with multiple sclerosis as measured with the Ashworth scale, but did result in some benefit in secondary outcome measures, assessing mobility and patients' perceptions of the effect of spasticity. These findings are consistent with those of smaller studies,13, 14, 15, 16 which showed some subjective, but no observer-verified, improvement in disease-related spasticity with use of cannabinoids. Our results should be considered in

References (37)

  • JA Sliwa

    Upper urinary tract abnormalities in multiple sclerosis

    Arch Phys Med Rehab

    (1996)
  • DW Paty et al.

    Multiple sclerosis

    (1998)
  • JC Hinson et al.

    Urodynamics and multiple sclerosis

    Urolog Clin N Am

    (1996)
  • DM Eisenberg et al.

    Trends in alternative medicine use in the United States, 1990–1997: results of a follow-up national survey

    JAMA

    (1998)
  • CE Schwartz et al.

    Utilisation of unconventional treatments by persons with MS: is it alternative or complementary?

    Neurology

    (1999)
  • P Consroe et al.

    The perceived effects of smoked cannabis on patients with multiple sclerosis

    Eur Neurol

    (1997)
  • Cannabis: the scientific and medical evidence (9th report)

    (1998)
  • LA Matsuda et al.

    Structure of a cannabinoid receptor and functional expression of the cloned cDNA

    Nature

    (1990)
  • S Munro et al.

    Molecular characterization of a peripheral receptor for cannabinoids

    Nature

    (1993)
  • WA Devane et al.

    Isolation and structure of a brain constituent that binds to the cannabinoid receptor

    Science

    (1992)
  • D Panikashvili et al.

    An endogenous cannabinoid (2-AG) is neuroprotective after brain injury

    Nature

    (2001)
  • AJ Thompson et al.

    Cannabinoids in MS: potentially useful but not just yet!

    Neurology

    (2002)
  • DJ Petro et al.

    Treatment of human spasticity with delta 9-tetrahydrocannabinol

    J Clin Pharmacol

    (1981)
  • JT Ungerleider et al.

    Delta 9 THC in the treatment of spasticity associated with multiple sclerosis

    Adv Alc Sub Abuse

    (1987)
  • HS Greenberg et al.

    Short-term effects of smoking marijuana on balance in patients with multiple sclerosis and normal volunteers

    Clin Pharmacol Ther

    (1994)
  • J Killestein et al.

    Safety, tolerability, and efficacy of orally administered cannabinoids in MS

    Neurology

    (2002)
  • SJW Evans et al.

    MINIM: minimisation program for allocating patients to treatments in clinical trials, Version 1.5

    (1990)
  • C Begg et al.

    A treatment allocation procedure for sequential clinical trials

    Biometrics

    (1980)
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